The clinical usefulness of the cannabinoids, including cannabidiol (“CBD”), to provide analgesia and neuroprotection, reduce inflammation, help alleviate nausea and emesis, as well as treat epilepsy, anxiety disorders, and glaucoma, has been well-recognized. In addition, it is also well-known that cannabidiol lacks the psychoactive effects seen in many of the other cannabinoids, including Δ9-tetrahydrocannabinol, which is currently available in an oral dosage, sold under the trade name Marinol®.
Pain is the most frequently reported symptom and it is a common clinical problem which confronts the clinician. Millions of people in the USA suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed. Similarly, millions of people also suffer from severe nausea and/or frequent emesis. Moreover, all too frequently, many patients suffering from chronic, under-treated or unretractable pain also suffer from lack of appetite, nausea and/or frequent emesis, such that a patient is unable to receive effective therapeutic doses of oral pain medications, thereby exacerbating their pain. Cannabinoids, including cannabidiol, are effective in alleviating pain. Moreover, cannabinoids, including cannabidiol, can reduce a patient's nausea and vomiting, independent of any pain relief achieved. Thus cannabinoids are particularly useful in patients experiencing nausea and vomiting secondarily to un- or under-treated pain.
A notable percentage of the U.S. population satisfy the diagnostic criteria for alcohol use disorders (“AUDs”). The consumption of excessive amounts of alcohol results in a complex array of pharmacological effects that directly impact the ability to treat the condition. These effects directly impact the brain and include progressive neurodegeneration, impaired executive function and dependence leading to withdrawal-induced negative effects. It is known that the cannabinoids, including cannabidiol, have neuroprotective, anxiolytic and anti-convulsant effects, which may be effective in preventing additional brain damage in persons with AUDs, while simultaneously decreasing the frequency of relapses.
Dystonia is a neurological movement disorder, with many known causes, and characterized by involuntary, continual muscular contractions causing twisting and repetitive movements or abnormal postures. Cannabinoids have been shown to reduce the symptoms of muscular contractions characterizing this disorder.
The etiological pathology of many diseases relates to the inflammatory processes caused by an individual's immune system. The inflammation may result from (1) an otherwise appropriate immunoresponse to an outside trauma, such as brain swelling secondary to a closed head injury; (2) an overactive immunoresponse such as with an allergic reaction or dermatitis; or (3) an inappropriate auto-immunoresponse such as what causes certain forms of multiple sclerosis, inflammatory bowel disorders and arthritis. Regardless of the underlying cause of the inflammation, it is therapeutically desirable under these circumstances to regulate the immune system and lessen the inflammatory response. Cannabinoids have been shown to regulate various steps in the immune response and could show some therapeutic benefit in treatment of certain inflammatory diseases such as psoriatic arthritis.
Rheumatoid arthritis affects approximately 0.5-1% of the United States population, and autoimmune diseases in general affect more than 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as adjunct treatment for rheumatoid arthritis and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.
In addition to the above-discussed therapeutics benefits, cannabinoids, cannabidiol, and cannabidiol prodrugs present a variety of pharmacological benefits, including, but not limited to, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective anti-cancer and immunomodulatory effects.
Given these systemic therapeutic benefits, it would be advantageous to develop a composition in which cannabidiol is delivered to achieve a therapeutically effective concentration in a patient. Unfortunately, as with the other cannabinoids, cannabidiol undergoes substantial first-pass metabolism when absorbed from the human gut after oral administration. Further, the oral bioavailability of any product is further diminished when a patient suffers from nausea or emesis, as either they avoid taking their oral medication or the oral dosage form does not remain in the GI tract for a sufficient amount of time to achieve a therapeutic dose.
Therefore, in view of the foregoing, it would be desirable to deliver therapeutically effective amounts of cannabidiol to a mammal in need thereof for the treatment of one or more medical conditions, such as pain, nausea or appetite stimulation, by a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal and not subject to first-pass metabolism upon absorption from the gastrointestinal tract. One non-oral route of administration for the systemic delivery of cannabidiol is transdermal.
Unfortunately, due to its highly hydrophobic nature, cannabidiol is poorly absorbed through membranes such as the skin of a mammal, such as a human. Therefore, the success of transdermally administering therapeutically effective quantities of cannabidiol to a mammal in need of such treatment within a reasonable time frame and over a suitable surface area has been substantially limited.
However, the epidermis and dermis of many mammals, such as humans and guinea pigs, contains enzymes which are capable of metabolizing active pharmaceutical agents which pass through the stratum corneum. The metabolic process occurring in the skin of mammals, such as humans, can be utilized to deliver pharmaceutically effective quantities of cannanbidiol to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabidiol that can be transdermally administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is systemically available for the treatment of a medical condition such as pain, nausea or appetite stimulation. Also described herein are compositions comprising cannabidiol prodrugs suitable for transdermal delivery to a mammal in need thereof and methods of using cannabidiol prodrugs.
Therefore, a significant advancement in the art would occur with the development of a cannabidiol prodrug capable of transdermal delivery; compositions suitable for transdermal delivery comprising prodrugs of cannabidiol; and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is locally or systemically available to a mammal in a therapeutically effective amount.
In addition, pharmaceutical compositions can be systemically administered by other means, including: oral, buccal, sublingual, injection, rectal, vaginal and intranasal. The metabolic process occurring in mammals, such as humans, can also be utilized to deliver pharmaceutically effective quantities of cannabidiol to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabidiol that can be administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is cannabidiol which is available for the treatment of a medical condition such as pain, nausea or appetite stimulation. Also described herein are compositions comprising cannabidiol prodrugs suitable for delivery to a mammal in need thereof and methods of using cannabidiol prodrugs.
Therefore, a significant advancement in the art would occur if one could develop a prodrug of cannabidiol capable of oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal or vaginal delivery; compositions suitable for oral, buccal, sublingual, injectable, topical, follicular, nasal, ocular, rectal, vaginal delivery comprising prodrugs of cannabidiol; and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is systemically available to a mammal in a therapeutically effective amount.
In addition to the benefits of systemically administered cannabidiol discussed above, cannabinoids, including cannabidiol, have been found to have localized benefits from topical administration. For example, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions originating near the surface of the skin, including but not limited to pain associated with post-herpetic neuralgia, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis and psoriatic arthritis. In addition, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions associated with deeper tissues, such as peripheral neuropathic pain, including but not limited to the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, and juvenile rheumatoid arthritis. When cannabinoids are administered topically to treat pain and other conditions associated with deeper tissues, including peripheral neuropathic pain, it maybe useful to co-administer cannabinoids systemically. Also, it has been found that the topical administration of cannabinoids, including cannabidiol, can inhibit the growth of hair.
In order to achieve these local benefits, it is advantageous for cannabidiol or a prodrug thereof to penetrate the stratum corneum but not be absorbed systemically. In such a case, the cannabidiol would concentrate in the skin and/or pilosebaceous unit, thus maximizing its local effect. Not only does the localized effect increase the potential therapeutic benefit, it lessens the frequency and severity of side-effects associated with cannabinoid administration because the amount of active compound circulating in the patient is minimized. The cannabidiol can be incorporated into a prodrug with an active moiety that would improve the appearance and/or hydration of the skin.
Therefore, a significant advancement in the art would occur with the development of a cannabidiol prodrug capable of topical delivery, such that it penetrates the outer layer of the skin but is not absorbed into circulation; compositions suitable for topical delivery comprising prodrugs of cannabidiol and methods of using prodrugs of cannabidiol whereby the resulting metabolic product was cannabidiol which is available at the site of administration in a mammal in a therapeutically effective amount but is not absorbed systemically.